Safety Profile of Oral Iron Chelator Deferiprone in Chinese Children with Transfusion-Dependent Thalassaemia.

UNLABELLED: There is a lack of knowledge regarding the incidence of serious adverse drug reactions (ADR) to the oral iron chelator deferiprone in Chinese children with transfusion-dependent thalassaemia. In this retrospective population-based cohort study, paediatric thalassaemia patients in Hong Kong were screened for serious and medically important adverse events related to deferiprone therapy using diagnosis codes, laboratory data and hospital admissions. Potential ADRs were assessed by reviewing concomitant medications, diagnoses and laboratory data and evaluated using standardised causality assessment. Eighty-seven patients contributing 169.8 person-years were included. Thirty ADRs were identified in 21 patients. Most ADRs (56.0%) occurred in the first three months of therapy. Neutropenia occurred in 11 patients (12.6%; incidence rate 6.5 per 100 patient-years) and severe neutropenia (agranulocytosis) was observed in 5 patients (5.7%, incidence rate 2.9 per 100 patient-years). Other identified ADRs involve severe arthropathy, elevated liver enzymes and mild thrombocytopenia. In conclusion, the safety profile of DFP therapy in Chinese children suffering from transfusion-dependent thalassaemia is in line with previous studies of non-Chinese children. However, unlike previous studies, we observed a relatively high incidence of agranulocytosis and neutropenia in patients with simultaneous combined therapy. Hence close monitoring for white blood cell counts is advised in Chinese children under combined iron chelation therapy. Further prospective clinical and pharmacogenetic studies are required to better evaluate this important safety signal. KEY POINTS: • Half of the identified ADRs related to deferiprone therapy occurred during the first three months of treatment. • A relatively high incidence of agranulocytosis and neutropenia. Hence close monitoring for white blood cell counts is advised in Chinese children under combined iron chelation therapy.

Testing the hypothesis that selenium deficiency is a risk factor for clozapine-induced agranulocytosis in rats.

Clozapine is an effective atypical antipsychotic associated with a relatively high incidence of drug-induced agranulocytosis. It forms a reactive nitrenium ion metabolite upon oxidation by peripheral neutrophils and their precursors in the bone marrow. Although the mechanism of this idiosyncratic drug reaction is still unknown, the observation that it does not occur rapidly on rechallenge of patients with a history of clozapine-induced agranulocytosis suggests that it is not immune-mediated. Previous studies by other research groups had found that patients on clozapine had lower plasma and red blood cell levels of selenium. The reactive metabolite of clozapine reacts with glutathione, and therefore, it is likely that it also binds to selenocysteine-containing proteins, such as glutathione peroxidase, thioredoxin reductase, and protein disulfide isomerase. We set out to test the hypothesis that clozapine-induced agranulocytosis is associated with selenium deficiency with rats on a selenium-deficient diet. We studied the effects of clozapine on selenium levels and the effect of selenium deficiency on leukocyte and neutrophil counts and clozapine covalent binding. We did not observe any significant difference between clozapine-treated rats given a selenium-adequate or deficient diet. Therefore, it is unlikely that selenium deficiency is a major risk factor for clozapine-induced agranulocytosis.

Double beta-lactam regimen compared to an aminoglycoside/beta-lactam regimen as empiric antibiotic therapy for febrile granulocytopenic cancer patients.

In a prospective, randomized trial, 205 febrile episodes in granulocytopenic cancer patients were treated with ceftazidime with or without tobramycin (C +/- T), both agents being administered only if the initial granulocyte count was below 200/microliters, or ceftazidime plus piperacillin (C + P). The overall response rate was 71% (39 of 60 for C +/- T and 45 of 58 for C + P). Logistic regression analyses documented no evidence of a significant difference between the two regimens in overall treatment effect after accounting for the linear effects of potentially important variables, such as infection type and granulocyte count. Although the response rates for the subgroup of patients with bacteremias was better with the C + P regimen (P = 0.06), there was no difference in response for patients with bacteremia and profound (< 100/microliters) sustained granulocytopenia. The double beta-lactam combination demonstrated in vitro synergism in 73%; antagonism was not seen. Both regimens produced excellent serum bactericidal levels (C +/- T geometric mean peak 1:170; C + P peak 1:137) against gram-negative but not gram-positive pathogens (1:4; 1:7 respectively) that had caused bacteremia. Emergence of resistance and significant coagulopathy and/or bleeding did not occur during therapy. Antibiotic-related nephrotoxicity was noted in 7 of 95 trials in the C + P and in 6 of 89 trials in the C +/- T group (P = 0.19). The incidence of secondary infections in patients with profound (< 100/microliters) sustained granulocytopenia was lower in the C +/- T group (P = 0.04). Alimentary canal anaerobic flora preservation with C +/- T, and suppression with C + P, was demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum bactericidal activity as a therapeutic guide in severely granulocytopenic patients with gram-negative septicemia.

The peak and trough levels of bactericidal activity of the serum of 74 severely granulocytopenic patients (less than or equal to 500 polymorphonucleates per microliter) with hematologic malignancies and Gram-negative septicemia were measured using the patient's infectious organism and serum containing the given antibiotics. When the peak titer of bactericidal activity in the serum was greater than 1:8 the septicemia was cured in more than 90% of the cases. However, in order to achieve a satisfactory rate of cure, patients with less than 100 polymorphonucleates/microliter required higher peak levels than patients with 100-500 polymorphonucleates/microliter. Serum bactericidal activity was influenced by the in vitro susceptibility of the offending pathogen and by the presence of in vitro synergism between the given antibiotics. These two variables showed a correlation with the clinical outcome that proved to be increasing with the degree of granulocytopenia. Furthermore, synergistic combination of the antibiotics appeared essential when the in vitro susceptibility shown by the offending pathogen was moderate. These data suggest (i) that determination of the bactericidal activity of the serum may prove to be a useful method to predict the clinical outcome in severely granulocytopenic patients with Gram-negative septicemia; and (ii) under the same conditions, antibiotic combinations that have demonstrable in vitro synergy against the offending pathogen should be given the utmost consideration.

Copper responsive anemia, induced by oral zinc therapy in a patient with acrodermatitis enteropathica.

Normocytic anemia with granulocytopenia occurred in a 23 year old man with acrodermatitis enteropathica who received high doses of zinc sulphate orally for 12 months. Copper deficiency was suspected to be the cause of this anemia when extreme hypocupremia and hypoceruloplasminemia were found. Oral zinc therapy was stopped and intravenous supplements of copper were followed by reticulocytosis and complete correction of the anemia and granulocytopenia. Plasma copper and ceruloplasmin levels normalized. Up to now copper deficiency has never been reported during zinc treatment in acrodermatitis enteropathica. We conclude that the copper status should be monitored during oral zinc therapy in this condition.

Alteration of colony-stimulating factor output, endotoxemia, and granulopoiesis in cyclic neutropenia.

Cellular and humoral factors involved in the regulation of granulopoiesis were evaluated in two patients with cyclic neutropenia by utilizing the agar-gel marrow culture technique to serially study marrow granulocytic colony-forming capacity (CFC) and the urinary output of colony-stimulating factor (CSF). CSF output varied inversely with peripheral neutrophil counts and directly with monocyte counts and evidence for infection (endotoxemia and/or staphylococcal abscesses). Following autologous infusion of one patient's plasma obtained during a period of neutropenia, increased urinary excretion of CSF occurred concomitant with increments in both marrow CFC and the proportion of granulocytic progenitor cells in DNA synthesis. Neutrophil periodicity was not altered by the administration of the neutropenic plasma. These findings are consistent with the hypothesis that cyclic neutropenia is caused by a quantitatively decreased entry of stem cells or granulocytic progenitor cells into granulopoiesis.